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The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many pesticides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used pesticides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, as well as quaternary ammonium compounds, the organic compound used in pesticides, piperonyl butoxide, as well as the insect repellent diethyltoluamide (DEET). We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose- dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, and dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, the pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonyl butoxide and DEET. Our study confirms potential developmental neurotoxicity of some pesticides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals.

Environmental Life Cycle Assessment is a pivotal guide to identifying environmental problems and reducing related impacts for companies and organizations in need of life cycle assessment (LCA). LCA, a unique sustainability tool, provides a framework that addresses a growing demand for practical technological solutions. Detailing each phase of the LCA methodology, this textbook covers the historical development of LCA, presents the general principles and characteristics of LCA, and outlines the corresponding standards for good practice determined by the International Organization for Standardization. It also explains how to identify the critical aspects of an LCA, provides detailed examples of LCA analysis and applications, and includes illustrated problems and solutions with concrete examples from water management, electronics, packaging, automotive, and other industries. In addition, readers will learn how to: Use consistent criteria to realize and evaluate an LCA independently of individual interests Understand the LCA methodology and become familiar with existing databases and methods based on the latest results of international research Analyze and critique a completed LCA Apply LCA methodology to simple case studies Geared toward graduate and undergraduate students studying environmental science and industrial ecology, as well as practicing environmental engineers, and sustainability professionals who want to teach themselves LCA good practices, Environmental Life Cycle Assessment demonstrates how to conduct environmental assessments for products throughout their life cycles. It presents existing methods and recent developments in the growing field of LCA and systematically covers goal and system definition, life cycle inventory, life cycle impact assessment, and interpretation.

© 2014 Elsevier Inc. All rights reserved, Within the European Environment and Health Action Plan an initiative to establish a coherent human biomonitoring approach in Europe was started. The project COPHES (COnsortium to Perform Human biomonitoring on a European Scale ) developed recommendations for a harmonized conduct of a human biomonitoring (HBM) survey which came into action as the pilot study DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale). Seventeen European countries conducted a survey with harmonized instruments for, inter alia, recruitment, fieldwork and sampling, in autumn/winter 2011/2012. Based on the countries' experiences of conducting the pilot study, following lessons learnt were compiled: the harmonized fieldwork instruments (basic questionnaire, urine and hair sampling) turned out to be very valuable for future HBM surveys on the European scale. A school approach was favoured by most of the countries to recruit school-aged children according to the established guidelines and country specific experiences. To avoid a low participation rate, intensive communication with the involved institutions and possible participants proved to be necessary. The communication material should also include information on exclusion criteria and offered incentives. Telephone contact to the participants the day before fieldwork during the survey can prevent the forgetting of appointments and first morning urine samples. To achieve comparable results on the European scale, training of interviewers in all issues of recruitment, fieldwork and sampling through information material and training sessions is crucial. A survey involving many European countries needs time for preparation and conduct. Materials for quality control prepared for all steps of recruitment, fieldwork and sampling proved to be important to warrant reliable results., The European Commission, DG for Research and Innovation (RTD) who funded COPHES in the 7th Framework programme (No. 244237) and DG Environment, who co-funded DEMOCOPHES under the LIFE+ Programme (50% – LIFE09 ENV/BE/000410) and partners from 21 countries.

© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/)., The metal cadmium (Cd) is a widespread environmental pollutant with documented adverse effects on the kidneys and bones from long-term environmental exposure, but with insufficiently elucidated public health consequences such as risk of cardiovascular disease, hormone-related cancer in adults and developmental effects in children. This study is the first pan-European human biomonitoring project that succeeded in performing harmonized measurements of Cd in urine in a comparable way in mother–child couples from 16 European countries. The aim of the study was to evaluate the overall Cd exposure and significant determinants of Cd exposure. A study population of 1632 women (24–52 years of age), and 1689 children (5–12 years of age), from 32 rural and urban areas, was examined within a core period of 6 months in 2011–2012. Women were stratified as smokers and non-smokers. As expected, smoking mothers had higher geometric mean (gm) urinary cadmium (UCd; 0.24 µg/g crea; n=360) than non-smoking mothers (gm 0.18 µg/g crea; n=1272; p, Financially supported by the 7th EU framework programe(DGResearch – No. 244237-COPHES),LIFE+ 2009(DG Environment – LIFE09ENV/BE000410-DEMOCOPHES),with addi- tional co-funding from DEMOCOPHES partners.

'Reproduced with permission from Environmental Health Perspectives', Background: For Europe as a whole, data on internal exposure to environmental chemicals do not yet exist. Characterization of the internal individual chemical environment is expected to enhance understanding of the environmental threats to health. Objectives: We developed and applied a harmonized protocol to collect comparable human biomonitoring data all over Europe. Methods: In 17 European countries, we measured mercury in hair and cotinine, phthalate metabolites, and cadmium in urine of 1,844 children (5–11 years of age) and their mothers. Specimens were collected over a 5-month period in 2011–2012. We obtained information on personal characteristics, environment, and lifestyle. We used the resulting database to compare concentrations of exposure biomarkers within Europe, to identify determinants of exposure, and to compare exposure biomarkers with healthbased guidelines. Results: Biomarker concentrations showed a wide variability in the European population. However, levels in children and mothers were highly correlated. Most biomarker concentrations were below the health-based guidance values. Conclusions: We have taken the first steps to assess personal chemical exposures in Europe as a whole. Key success factors were the harmonized protocol development, intensive training and capacity building for field work, chemical analysis and communication, as well as stringent quality control programs for chemical and data analysis. Our project demonstrates the feasibility of a Europe-wide human biomonitoring framework to support the decision-making process of environmental measures to protect public health., The research leading to these results received funding for the COPHES project (COnsortium to Perform Human biomonitoring on a European Scale) from the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement 244237. DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) was co-funded (50%:50%) by the European Commission LIFE+ Programme (LIFE09/ENV/BE/000410) and the partners. For information on both projects as well as on the national co-funding institutions, see http://www.eu-hbm.info/. The sponsors had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

© 2014 Elsevier Inc. All rights reserved., In 2011 and 2012,the COPHES/DEMOCOPHES twin projects performedt he first ever harmonized human biomonitoring survey in 17 European countries.In more than 1800 mother–child pairs,individual lifestyle data were collected and cadmium,cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples.While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures,the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle.In general,13 countries having implemented DEMOCOPHES provided high quality data from external sources that were relevant for interpretation purposes.However,some data were not available for reporting or were not in line with predefined specifications. Therefore,only part of the external information could be included in the statistical analyses. Nonetheless,there was a highly significant correlation between national levels of fish consumption and mercury in hair,the strength of antismoking legislation was significantly related to urinary cotinine levels,and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality.These results again show the potential of biomonitoring data to provide added value for(the evaluation of)evidence-informed policy making., The European Commission,Belgium,DG for Research and Innovation(RTD),who is funding COPHES in the 7th Framework Programme(No.244237).DEMOCOPHES(LIFE09ENV/BE/000410)received 50% funding through the LIFE+ financial instrument of the European Union(DGENV),as well as 50% through funding received from the DEMOCOPHES partners.

The development of methodologies to assess the effects of pesticides in a consistent way and to enable comparison with the impacts from other agricultural practices is urgently needed. This paper describes a life cycle assessment method to determine the impact of pesticides on human health and ecosystems. The approach considers a full-fate analysis and the exposure to toxic pollutants through different media and pathways, including residues in food, based on the behavior of the pesticides in air and the importance of transfers between soil and surface or ground waters. For human toxicity, estimates of pesticide residues show that food intake results in the highest toxic exposure, about 10 3 to 10 5 times higher than that induced by drinking water or inhalation. Better evaluation practices of pesticide residues in food need to be established in priority. For the “no effect concentration (NEC)” used as a reference for both terrestrial and aquatic ecotoxicity, extrapolation methods are developed on the basis of experimental data. Extrapolation coefficients for risk assessment are to be used with caution; an intra-species extrapolation factor of 10 explained the relationship between acute (LC 50 ) and chronic (NOEC) ecotoxicity, whereas it was not suitable for inter-species extrapolation. The method is applied to a case study of five fungicides that have the same function on wheat. Results obtained for the 100 most commonly used pesticides in Switzerland are presented. It is demonstrated that the comparison of pesticides is feasible, the pollution sources of highest concern being identifiable and the best environmental management practices thereby promoted without penalizing the crop itself.

In Part 1 of this article we developed an approach for the calculation of cancer effect measures for life cycle assessment (LCA). In this article, we propose and evaluate the method for the screening of noncancer toxicological health effects. This approach draws on the noncancer health risk assessment concept of benchmark dose, while noting important differences with regulatory applications in the objectives of an LCA study. We adopt the centraltendency estimate of the toxicological effect dose inducing a 10% response over background, ED10, to provide a consistent point of departure for default linear low-dose response estimates (betaED10). This explicit estimation of low-dose risks, while necessary in LCA, is in marked contrast to many traditional procedures for noncancer assessments. For pragmatic reasons, mechanistic thresholds and nonlinear low-dose response curves were not implemented in the presented framework. In essence, for the comparative needs of LCA, we propose that one initially screens alternative activities or products on the degree to which the associated chemical emissions erode their margins of exposure, which may or may not be manifested as increases in disease incidence. We illustrate the method here by deriving the betaED10 slope factors from bioassay data for 12 chemicals and outline some of the possibilities for extrapolation from other more readily available measures, such as the no observable adverse effect levels (NOAEL), avoiding uncertainty factors that lead to inconsistent degrees of conservatism from chemical to chemical. These extrapolations facilitated the initial calculation of slope factors for an additional 403 compounds; ranging from 10(-6) to 10(3) (risk per mg/kg-day dose). The potential consequences of the effects are taken into account in a preliminary approach by combining the betaED10 with the severity measure disability adjusted life years (DALY), providing a screening-level estimate of the potential consequences associated with exposures, integrated over time and space, to a given mass of chemical released into the environment for use in LCA.

© 2014 Elsevier Inc. All rights reserved., In 2004 the European Commission and Member States initiated activities towards a harmonized approach for Human Biomonitoring surveys throughout Europe. The main bjective was to sustain environmental health policy by building a coherent and sustainable framework and by increasing the comparability of data across countries. A pilot study to test common guidelines for setting up surveys was considered a key step in this process. Through a bottom-up approach that included all stakeholders, a joint study protocol was elaborated. From September 2011 till February 2012, 17 European countries collected data from 1844 mother–child pairs in the frame of DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES).1 Mercury in hair and urinary cadmium and cotinine were selected as biomarkers of exposure covered by sufficient analytical experience. Phthalate metabolites and Bisphenol A in urine were added to take into account increasing public and political awareness for emerging types of contaminants and to test less advanced markers/markers covered by less analytical experience. Extensive efforts towards chemo-analytical comparability were included. The pilot study showed that common approaches can be found in a context of considerable differences with respect to experience and expertize, socio-cultural background, economic situation and national priorities. It also evidenced that comparable Human Biomonitoring results can be obtained in such context. A European network was built, exchanging information, expertize and experiences, and providing training on all aspects of a survey. A key challenge was finding the right balance between a rigid structure allowing maximal comparability and a flexible approach increasing feasibility and capacity building. Next steps in European harmonization in Human Biomonitoring surveys include the establishment of a joint process for prioritization of substances to cover and biomarkers to develop, linking biomonitoring surveys with health examination surveys and with research, and coping with the diverse implementations of EU regulations and international guidelines with respect to ethics and privacy., Financial support: COPHES (COnsortium to Perform Human Biomonitoring on a European Scale) was funded by the Seventh EU Framework Programme 2007–2011 under grant agreement no [244237]. DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale) was co-funded (50%:50%) by the European Commission LIFE+ Programme (LIFE09/ENV/BE/000410) and the partners.

Objective: Many pesticides including pyrethroids and azole fungicides are suspected to have an endocrine disrupting property. At present, the joint activity of compound mixtures is only marginally known. Here we tested the hypothesis that the antiandrogenic activity of mixtures of azole fungicides can be predicted by the concentration addition (CA) model. Methods: The antiandrogenic activity was assessed in MDA-kb2 cells. Following assessing single compounds activities mixtures of azole fungicides and vinclozolin were investigated. Interactions were analyzed by direct comparison between experimental and estimated dose–response curves assuming CA, followed by an analysis by the isobole method and the toxic unit approach. Results: The antiandrogenic activity of pyrethroids deltamethrin, cypermethrin, fenvalerate and permethrin was weak, while the azole fungicides tebuconazole, propiconazole, epoxiconazole, econazole and vinclozolin exhibited strong antiandrogenic activity. Ten binary and one ternary mixture combinations of five antiandrogenic fungicides were assessed at equi-effective concentrations of EC{sub 25} and EC{sub 50}. Isoboles indicated that about 50% of the binary mixtures were additive and 50% synergistic. Synergism was even more frequently indicated by the toxic unit approach. Conclusion: Our data lead to the conclusion that interactions in mixtures follow the CA model. However, a surprisingly high percentage of synergistic interactions occurred. Therefore, themore » mixture activity of antiandrogenic azole fungicides is at least additive. Practice: Mixtures should also be considered for additive antiandrogenic activity in hazard and risk assessment. Implications: Our evaluation provides an appropriate “proof of concept”, but whether it equally translates to in vivo effects should further be investigated. - Highlights: • Humans are exposed to pesticide mixtures such as pyrethroids and azole fungicides. • We assessed the antiandrogenicity of pyrethroids and azole fungizides. • Many azole fungicides showed significant antiandrogenic activity . • Many binary mixtures of antiandrogenic azole fungicides showed synergistic interactions. • Concentration addition of pesticides in mixtures should be considered.« less

© 2013 Elsevier GmbH. All rights reserved., COPHES/DEMOCOPHES has its origins in the European Environment and Health Action Plan of 2004 to “develop a coherent approach on human biomonitoring (HBM) in Europe”. Within this twin-project it was targeted to collect specimens from 120 mother–child-pairs in each of the 17 participating Europeancountries. These specimens were investigated for six biomarkers (mercury in hair; creatinine, cotinine,cadmium, phthalate metabolites and bisphenol A in urine). The results for mercury in hair are described in a separate paper. Each participating member state was requested to contract laboratories, for capacity building reasons ideally within its borders, carrying out the chemical analyses. To ensure comparability of analytical data a Quality Assurance Unit (QAU) was established which provided the participating laboratories with standard operating procedures (SOP) and with control material. This material was specially prepared from native, non-spiked, pooled urine samples and was tested for homogeneity and stability.Four external quality assessment exercises were carried out. Highly esteemed laboratories from all over the world served as reference laboratories. Web conferences after each external quality assessment exercise functioned as a new and effective tool to improve analytical performance, to build capacity and to educate less experienced laboratories. Of the 38 laboratories participating in the quality assurance exercises 14 laboratories qualified for cadmium, 14 for creatinine, 9 for cotinine, 7 for phthalate metabolitesand 5 for bisphenol A in urine. In the last of the four external quality assessment exercises the laboratories that qualified for DEMOCOPHES performed the determinations in urine with relative standard deviations(low/high concentration) of 18.0/2.1% for cotinine, 14.8/5.1% for cadmium, 4.7/3.4% for creatinine. Relative standard deviations for the newly emerging biomarkers were higher, with values between 13.5 and 20.5% for bisphenol A and between 18.9 and 45.3% for the phthalate metabolites. Plausibility control of the HBM results of all participating countries disclosed analytical shortcomings in the determination of Cd when using certain ICP/MS methods. Results were corrected by reanalyzes. The COPHES/DEMOCOPHESproject for the first time succeeded in performing a harmonized pan-European HBM project. All data raised have to be regarded as utmost reliable according to the highest international state of the art, since highly renowned laboratories functioned as reference laboratories. The procedure described here, that has shown its success, can be used as a blueprint for future transnational, multicentre HBM projects., COPHES is funded under the 7th frameworkprogram of the EU (DG Research – No. 244237). DEMO-COPHES is funded 50% by Life+ 2009 (DG Environment – Life09ENV/BE000410) and the corresponding authorities in the participating countries.

© 2014 Elsevier Inc. All rights reserved., The potential of Human Biomonitoring (HBM) in exposure characterisation and risk assessment is well established in the scientific HBM community and regulatory arena by many publications. The European Environment and Health Strategy as well as the Environment and Health Action Plan 2004-2010 of the European Commission recognised the value of HBM and the relevance and importance of coordination of HBM programmes in Europe. Based on existing and planned HBM projects and programmes of work and capabilities in Europe the Seventh Framework Programme (FP 7) funded COPHES (COnsortium to Perform Human Biomonitoring on a European Scale) to advance and improve comparability of HBM data across Europe. The pilot study protocol was tested in 17 European countries in the DEMOCOPHES feasibility study (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) cofunded (50%) under the LIFE+ programme of the European Commission. The potential of HBM in supporting and evaluating policy making (including e.g. REACH) and in awareness raising on environmental health, should significantly advance the process towards a fully operational, continuous, sustainable and scientifically based EU HBM programme. From a number of stakeholder activities during the past 10 years and the national engagement, a framework for sustainable HBM structure in Europe is recommended involving national institutions within environment, health and food as well as European institutions such as ECHA, EEA, and EFSA. An economic frame with shared cost implications for national and European institutions is suggested benefitting from the capacity building set up by COPHES/DEMOCOPHES., COPHES was coordinated by BiPRO GmbH, Germany, with the University of Leuven, Belgium and was funded by DG Research in the Seventh Framework Programme (FP7/2007-2013). DEMOCOPHES (LIFE09 ENV/BE/000410) was coordinated by the Federal Public Service Health, Food Chain Safety and Environment, Belgium and was jointly financed by the European Commission LIFE┼ programme (50%) and national institutions in each participating country.

Systems using rain water or reducing water consumption have been recently developed as an alternative to conventional toilet flushing. This article aims to quantify the environmental impacts of these systems and to identify key factors in each system. A Life Cycle Assessment (LCA) has been carried out to reach these goals. Scenarios with conventional water supplies present a lower energy requirement and lower environmental loads than recuperation scenarios. Sensitivity analyses indicate that recuperation is energetically favourable only when the energy required for the water supply is higher than 0.8 kWh/m 3 ;, assuming a complex drinking water treatment. The study also reveals that low-flow toilets should be promoted as they lead to significant reductions in energy consumption and in pollutant emissions. A combination of a conventional water supply and low water consumption (scenario CONVeco) is advantageous for all environmental problems.

The inclusion of fate and exposure is a central issue in Life Cycle Impact Assessment (LCIA). According to the framework developed by the Society of Environmental Toxicity and Chemistry (SETAC), fate and exposure route are included through a fate coefficient which makes the link between an emission and the related increase in concentration. In the Critical surface-time 95 methodology, fate factors of air pollutants are determined empirically at a world level as the ratio of measured concentration to the total estimated emission flow. Based on a detailed study performed for seventeen pollutants, a correlation is developed to predict fate factors from the residence time. Variation of a factor 10000 arc observed for the fate coefficient. Empirical fate factors are compared to modelled fate factors and are found to have a similar order of magnitude

Currently, the public has access to a variety of databases containing mutagenicity and carcinogenicity data. These resources are crucial for the toxicologists and regulators involved in the risk assessment of chemicals, which necessitates access to all the relevant literature, and the capability to search across toxicity databases using both biological and chemical criteria. Towards the larger goal of screening chemicals for a wide range of toxicity end points of potential interest, publicly available resources across a large spectrum of biological and chemical data space must be effectively harnessed with current and evolving information technologies (i.e. systematised, integrated and mined), if long-term screening and prediction objectives are to be achieved. A key to rapid progress in the field of chemical toxicity databases is that of combining information technology with the chemical structure as identifier of the molecules. This permits an enormous range of operations (e.g. retrieving chemicals or chemical classes, describing the content of databases, finding similar chemicals, crossing biological and chemical interrogations, etc.) that other more classical databases cannot allow. This article describes the progress in the technology of toxicity databases, including the concepts of Chemical Relational Database and Toxicological Standardized Controlled Vocabularies (Ontology). Then it describes the ISSTOX cluster of toxicological databases at the Istituto Superiore di Sanita. It consists of freely available databases characterised by the use of modern information technologies and by curation of the quality of the biological data. Finally, this article provides examples of analyses and results made possible by ISSTOX.

Phthalates and bisphenol A have very widespread use leading to significant exposure of humans. They are suspected to interfere with the endocrine system, including the androgen, estrogen and the thyroid hormone system. Here we analyzed the antiandrogenic activity of six binary, and one ternary mixture of phthalates exhibiting complete antiandrogenic dose-response curves, and binary mixtures of phthalates and bisphenol A at equi-effective concentrations of EC(10), EC(25) and EC(50) in MDA-kb2 cells. Mixture activity followed the concentration addition (CA) model with a tendency to synergism at high and antagonism at low concentrations. Isoboles and the toxic unit approach (TUA) confirmed the additive to synergistic activity of the binary mixtures BBP+DBP, DBP+DEP and DEP+BPA at high concentrations. Both methods indicate a tendency to antagonism for the EC(10) mixtures BBP+DBP, BBP+DEP and DBP+DEP, and the EC(25) mixture of DBP+BPA. A ternary mixture revealed synergism at the EC(50), and weak antagonistic activity at the EC(25) level by the TUA. A mixture of five phthalates representing a human urine composition and reflecting exposure to corresponding parent compounds showed no antiandrogenic activity. Our study demonstrates that CA is an appropriate concept to account for mixture effects of antiandrogenic phthalates and bisphenol A. The interaction indicates a departure from additivity to antagonism at low concentrations, probably due to interaction with the androgen receptor and/or cofactors. This study emphasizes that a risk assessment of phthalates should account for mixture effects by applying the CA concept.

This paper presents a new curated database on in vivo micronucleus mutagenicity results, called ISSMIC. It is freely available at: http://www.iss.it/ampp/dati/cont.php?id5233&lang51&tipo57. The experimental results were critically reviewed, and evidence on target cell exposure was considered as well. The inspection of ISSMIC demonstrates that a large proportion of reported negative results in the literature (231 out 566 ISSMIC chemicals) lack a clear-cut, direct demonstration of toxicity at the target cells. Using this updated database, the predictive value of a compilation of Structural Alerts (SA) for in vivo micronucleus recently implemented in the expert system Toxtree was investigated. Individually, most of the SA showed a high Positive Predictivity (� 80%), but the need for further expanding the list of alerts was pointed out as well. The role of in vivo micronucleus in strategies for carcinogenicity prediction was re-evaluated. In agreement with previous analyses, the data point to a low overall correlation with carcinogenicity. In addition, given the cost in animal lives and the time required for the experimentation, in many programs, the in vivo tests are used only to assess in vitro positive results. The ability of in vivo micronucleus to identify real positives (i.e. carcinogens) among chemicals positive in Salmonella or among chemicals inducing in vitro chromosomal aberrations was studied. It appears that the in vivo micronucleus test does not have added value and rather impairs the prediction ability of the in vitro tests alone. The overall evidence indicates that in vivo micronucleus—in its present form—cannot be considered an useful tool for routine genotoxicity testing but should be used in targeted mechanistic studies.

Contaminants including flame retardants, antimicrobial agents and phthalates, occurring as residues in human tissues were associated with altered endocrine function. In our study we analysed the flame retardants tetrabromobisphenol A (TBBPA), hexabromocyclodecane (HBCD), penta-bromodiphenylether (BDE-100) and hexa-BDE (BDE-155), the antimicrobial compounds triclosan (TCS) and triclocarban (TCC) and eight phthalates for their androgenic and antiandrogenic activity in vitro in the MDA-kb2 cell line. No or only weak androgenic activity was observed for all the tested compounds. TBBPA showed weak antiandrogenic activity, which was demonstrated for the first time. The flame retardants HBCD, BDE-100 and BDE-155 enhanced the dihydrotestosterone-dependent activation of androgen receptor-responsive gene expression but exhibited little or no agonistic activity. The enhancement reached 150%, which was similar to the antimicrobials (TCS up to 180%, and TCC up to 130%). This enhancement of androgenic activity represents a novel mode of action of the endocrine activity of flame retardants. In contrast, most phthalates showed antiandrogenic activity. Butylbenzyl phthalate (BBP), dibutyl phthalate (DBP) and diethyl phthalate (DEP) showed strong antiandrogenicity, whereas the action of diethylhexyl phthalate (DEHP), dipentyl phthalate (DPP), dimethyl phthalate (DMP), and the DEHP metabolite monoethylhexyl phthalate (MEHP) was lower. Our in vitro study demonstrates for the first time a weak antiandrogenic activity of TBBPA, and a significant enhancement of the androgenic activity of HBCD, BDE-100 and BDE-155, which represents a novel mechanism of hormonal activity of flame retardants.

The two-year rodent bioassay represents the golden standard for evaluating the carcinogenicity of chemicals. Because of practical and ethical reasons, alternative approaches have been investigated for many years. Among these approaches, the (quantitative) structure-activity relationships [(Q)SARs] offer promising perspectives for quickly screening a large number of chemicals. To increase the acceptance of (Q)SARs among the regulators, their predictive power needs to be scientifically validated. In this article, we tested the capacity of the DEREKfW expert system to qualitatively predict the rodent carcinogenicity and the genotoxic potential of 60 pesticides recently registered in Switzerland. The percentage of false negatives was found to be 31% for carcinogenicity. The associated sensitivity of 69% indicates that most of the pesticides with positive rodent bioassay results were detected by DEREKfW. On the other hand, the low specificity of 47% indicates that many pesticides may be flagged as carcinogenic while rodent bioassays would not confirm this potential. This may lead to unnecessary testing or the unnecessary restriction of a chemical.

In Part 1 of this article we developed an approach for the calculation of cancer effect measures for life cycle assessment (LCA). In this article, we propose and evaluate the method for the screening of noncancer toxicological health effects. This approach draws on the noncancer health risk assessment concept of benchmark dose, while noting important differences with regulatory applications in the objectives of an LCA study. We adopt the centraltendency estimate of the toxicological effect dose inducing a 10% response over background, ED10, to provide a consistent point of departure for default linear low-dose response estimates (betaED10). This explicit estimation of low-dose risks, while necessary in LCA, is in marked contrast to many traditional procedures for noncancer assessments. For pragmatic reasons, mechanistic thresholds and nonlinear low-dose response curves were not implemented in the presented framework. In essence, for the comparative needs of LCA, we propose that one initially screens alternative activities or products on the degree to which the associated chemical emissions erode their margins of exposure, which may or may not be manifested as increases in disease incidence. We illustrate the method here by deriving the betaED10 slope factors from bioassay data for 12 chemicals and outline some of the possibilities for extrapolation from other more readily available measures, such as the no observable adverse effect levels (NOAEL), avoiding uncertainty factors that lead to inconsistent degrees of conservatism from chemical to chemical. These extrapolations facilitated the initial calculation of slope factors for an additional 403 compounds; ranging from 10(-6) to 10(3) (risk per mg/kg-day dose). The potential consequences of the effects are taken into account in a preliminary approach by combining the betaED10 with the severity measure disability adjusted life years (DALY), providing a screening-level estimate of the potential consequences associated with exposures, integrated over time and space, to a given mass of chemical released into the environment for use in LCA.

PP-19 EVALUATION OF SPERM QUALITY AT A NATIONAL LEVEL: LOGISTIC, RECRUITMENT, ANALYTICAL AND STATISTICAL PROBLEMS ENCOUNTERED IN SWITZERLAND Josefina Vargas1, Roumen Parapanov1, Marc Van Den Bergh2, Eric Stettler3, Pierre Crettaz4, Alfred Senn1, Marc Germond1. 1Fondation Faber, Lausanne, Switzerland, 2Kantonspital Baden Ag, Fertilitatslabor, Switzerland, 3Swiss Army Medical Services, Switzerland, 4Federal Office of Public Health, Switzerland